tbuckley/cabot-search huggingface dataset:
Self-assembly of X-shaped antibody to combine the activity of IgG and IgA for enhanced tumor killing
Authors: Yuexia Liang, Xin Li, Fengping Peng, Xiaohan Ye, Wei Wang, Tianyi Cen, Fan Li, Yue Lu, Zhaoyun Liu, Hui Liu, Kai Ding, Kai Ye, Yang Yu, Tianyu Ma, Sihe Zhang, Yi Huang, Yuan Wang, Xue Yang, Rong Fu, Hongkai Zhang
Journal: Theranostics (2022)

Rationale: IgA can induce activation of neutrophils which are the most abundant cell type in blood, but the development of IgA as therapeutic has been confounded by its short half-life and a weak ability to recruit NK cells as effector cells. Therefore, we generated an X-shaped antibody (X-body) based on the principle of molecular self-assembly that combines the activities of both IgG and IgA, which can effectively recruit and activate NK cells, macrophages, and neutrophils to kill tumor cells. Methods: X-body was generated by using a self-assembly strategy. The affinity of the X-body with the antigen and Fc receptors was tested by surface plasmon resonance. The shape of X-body was examined using negative staining transmission electron microscopy. The tumor cell killing activity of X-body was assessed in vitro and in multiple syngeneic mouse models. To explore the mechanism of X-body, tumor-infiltrating immune cells were analyzed by single-cell RNA-seq and flow cytometry. The dependence of neutrophil, macrophage, and NK cells for the X-body efficacy was confirmed by in vivo depletion of immune cell subsets. Results: The X-body versions of rituximab and trastuzumab combined the full spectrum activity of IgG and IgA and recruited NK cells, macrophages, and neutrophils as effector cells for eradication of tumor cells. Treatment with anti-hCD20 and anti-hHER2 X-bodies leads to a greater reduction in tumor burden in tumor-bearing mice compared with the IgA or IgG counterpart, and no obvious adverse effect is observed upon X-body treatment. Moreover, the X-body has a serum half-life and drug stability comparable to IgG. Conclusions: The X-body, as a myeloid-cell-centered therapeutic strategy, holds promise for the development of more effective cancer-targeting therapies than the current state of the art.
Clearance pathways of near-infrared-II contrast agents
Authors: Sha Yang, Na Li, Hao Xiao, Gui-long Wu, Fen Liu, Pan Qi, Li Tang, Xiaofeng Tan, Qinglai Yang
Journal: Theranostics (2022)

Near-infrared-II (NIR-II) bioimaging gradually becomes a vital visualization modality in the real-time investigation for fundamental biological research and clinical applications.The favorable NIR-II contrast agents are vital in NIR-II imaging technology for clinical translation, which demands good optical properties and biocompatibility.Nevertheless, most NIR-II contrast agents cannot be applied to clinical translation due to the acute or chronic toxicity caused by organ retention in vivo imaging.Therefore, it is critical to understand the pharmacokinetic properties and optimize the clearance pathways of NIR-II contrast agents in vivo to minimize toxicity by decreasing organ retention.In this review, the clearance mechanisms of biomaterials, including renal clearance, hepatobiliary clearance, and mononuclear phagocytic system (MPS) clearance, are synthetically discussed.The clearance pathways of NIR-II contrast agents (classified as inorganic, organic, and other complex materials) are highlighted.Successively analyzing each contrast agent barrier, this review guides further development of the clearable and biocompatible NIR-II contrast agents.
Janus USPION modular platform (JUMP) for theranostic ultrasound-mediated targeted intratumoral microvascular imaging and DNA/miRNA delivery
Authors: Ragnhild D. Whitaker, Julius L. Decano, Catherine Gormley, Carl A. Beigie, Cari Meisel, Glaiza A. Tan, Ann-Marie Moran, Nicholas J. Giordano, Yoonjee Park, Peng Huang, Sean Andersson, Donald Gantz, Aaron K. Grant, Nelson Ruiz-Opazo, Victoria L.M. Herrera, Joyce Y. Wong
Journal: Theranostics (2022)

Rationale: High mortality in pancreatic cancer (PDAC) and triple negative breast cancer (TNBC) highlight the need to capitalize on nanoscale-design advantages for multifunctional diagnostics and therapies.DNA/RNA-therapies can provide potential breakthroughs, however, to date, there is no FDA-approved systemic delivery system to solid tumors.Methods: Here, we report a Janus-nanoparticle (jNP)-system with modular targeting, payload-delivery, and targeted-imaging capabilities.Our jNP-system consists of 10 nm ultrasmall superparamagnetic iron oxide nanoparticles (USPION) with opposing antibody-targeting and DNA/RNA payload-protecting faces, directionally self-assembled with commercially available zwitterionic microbubbles (MBs) and DNA/RNA payloads.Results: Sonoporation of targeted jNP-payload-MBs delivers functional reporter-DNA imparting tumorfluorescence, and micro-RNA126 reducing non-druggable KRAS in PDAC-Panc1 and TNBC-MB231 xenografted tumors.The targeting jNP-system enhances ultrasound-imaging of intra-tumoral microvasculature using less MBs/body weight (BW).The jNP-design enhances USPION's T2*-magnetic resonance (MR) and MR-imaging of PDAC-peritoneal metastases using less Fe/BW.Conclusion: Altogether, data advance the asymmetric jNP-design as a potential theranostic Janus-USPION Modular Platform -a JUMP forward.
Deep brain stimulation by blood–brain-barrier-crossing piezoelectric nanoparticles generating current and nitric oxide under focused ultrasound
Authors: Taejeong Kim, Hyun Jin Kim, Wonseok Choi, Yeong Mi Lee, Jung Hyun Pyo, Junseok Lee, Jeesu Kim, Jihoon Kim, Joung-Hun Kim, Chulhong Kim, Won Jong Kim
Journal: Nature Biomedical Engineering (2022)
A Novel Her2/VEGFR2/CD3 trispecific antibody with an optimal structural design showed improved T-cell-redirecting antitumor efficacy
Authors: Dong Liu, Xuexiu Qi, Xiaoyi Wei, Lijun Zhao, Xuechun Wang, Shuhong Li, Zhidong Wang, Licai Shi, Jiean Xu, Mei Hong, Zhong Liu, Lili Zhao, Xiankun Wang, Bo Zhang, Yuhan Zhang, Feng Wang, Yu J. Cao
Journal: Theranostics (2022)

Rationale: T-cell-redirecting bispecific antibodies (bsAbs) and trispecific antibodies (tsAbs) designed to recognize different epitopes or antigens have emerged as promising cancer therapies.Current approaches are all designed to include another antibody specific to the site of the primary antibody, and the molecular structures are generally established.However, the dimensions of target molecule and epitope location play a key role in the efficiency of the immunological synapse (IS) formation and subsequent T-cell-redirecting activities, therefore the connection flexibility of these antibodies determines the geometries of different formats of these molecules and will have a major impact on the efficacy.Methods: We describe a novel recombination strategy using various linker designs to site-specifically fuse anti-Her2 (2Rs15) or anti-VEGFR2 (3VGR19) nanobodies to different positions of the anti-CD3 antibody fragment (Fab, SP34).Based on the comparison among the various antigen-specific bsAbs, we could determine the desired fusion site of each nanobody to SP34, and further ensure the optimal structure of tsAbs with synergistic dual-antigen enhanced T-cell-redirecting activities.Results: This approach allows precise control of the formation of IS between Her2-and/or VEGFR2expressing cancer cells and T cells, to obtain the optimal structure of the Her2/VEGFR2/CD3 tsAb without the need to map antibody-binding epitopes.Optimization of Her2/VEGFR2/CD3 tsAb results in enhanced T-cell-redirecting in vitro and in vivo antitumor efficacy compared with the corresponding bsAbs alone or in combination, and the potency to overcome tumor relapse due to antigen escape or resistance to Herceptin and Cyramza therapy. Conclusion:The novel design strategy for developing tsAbs using a site-specific recombination approach represents a promising platform for immuno-oncology and in applications other than cancer therapy.
Mutant NPM1 Directly Regulates Oncogenic Transcription in Acute Myeloid Leukemia
Authors: Hannah J. Uckelmann, Elena L. Haarer, Reina Takeda, Eric M. Wong, Charlie Hatton, Christian Marinaccio, Florian Perner, Masooma Rajput, Noa J.C. Antonissen, Yanhe Wen, Lu Yang, Lorenzo Brunetti, Chun-Wei Chen, Scott A. Armstrong
Journal: Cancer Discovery (2022)

The dysregulation of developmental and stem cell-associated genes is a common phenomenon during cancer development. Around half of patients with acute myeloid leukemia (AML) express high levels of HOXA cluster genes and MEIS1. Most of these AML cases harbor an NPM1 mutation (NPM1c), which encodes for an oncoprotein mislocalized from the nucleolus to the cytoplasm. How NPM1c expression in hematopoietic cells leads to its characteristic gene-expression pattern remains unclear. Here, we show that NPM1c directly binds to specific chromatin targets, which are co-occupied by the histone methyltransferase KMT2A (MLL1). Targeted degradation of NPM1c leads to a rapid decrease in gene expression and loss of RNA polymerase II, as well as activating histone modifications at its targets. We demonstrate that NPM1c directly regulates oncogenic gene expression in collaboration with the MLL1 complex and define the mechanism by which MLL1-Menin small-molecule inhibitors produce clinical responses in patients with NPM1-mutated AML. We uncovered an important functional role of mutant NPM1 as a crucial direct driver of oncogenic gene expression in AML. NPM1c can bind to chromatin and cooperate with the MLL complex, providing the first functional insight into the mechanism of Menin-MLL inhibition in NPM1c leukemias. See related article by Wang et al., p. 724. This article is highlighted in the In This Issue feature, p. 517.
The Characteristics of Patients With <scp>COVID</scp>‐19–Associated Pediatric Vasculitis: An International, Multicenter Study
Authors: Ezgi D. Batu, Seher Sener, Gulcan Ozomay Baykal, Elif Arslanoglu Aydin, Semanur Özdel, Alenka Gagro, Esra Esen, Merav Heshin‐Bekenstein, Nilüfer Akpınar Tekgöz, Fatma G. Demirkan, Kubra Ozturk, Olga Vougiouka, H. Emine Sonmez, Maria Cristina Maggio, Ummusen Kaya Akca, Marija Jelusic, Aysenur Pac Kısaarslan, Banu Acar, Nuray Aktay Ayaz, Betül Sözeri, Seza Özen
Journal: Arthritis & Rheumatology (2022)

COVID-19-associated pediatric vasculitis, other than Kawasaki disease (KD)-like vasculitis in multisystem inflammatory syndrome in children (MIS-C), is very rare. This study sought to analyze the characteristics, treatment, and outcomes in patients with COVID-19-associated pediatric vasculitis (excluding KD-like vasculitis in MIS-C).The inclusion criteria were as follows: 1) age <18 years at vasculitis onset; 2) evidence of vasculitis; 3) evidence of SARS-CoV-2 exposure; and 4) ≤3 months between SARS-CoV-2 exposure and vasculitis onset. Patients with MIS-C were excluded. The features of the subset of patients in our cohort who had COVID-19-associated pediatric IgA vasculitis/Henoch Schönlein purpura (IgAV/HSP) were compared against a pre-pandemic cohort of pediatric IgAV/HSP patients.Forty-one patients (median age 8.3 years; male to female ratio 1.3) were included from 14 centers and 6 countries. The most frequent vasculitis subtype was IgAV/HSP (n = 30). The median duration between SARS-CoV-2 exposure and vasculitis onset was 13 days. Involvement of the skin (92.7%) and of the gastrointestinal system (61%) were the most common manifestations of vasculitis. Most patients (68.3%) received glucocorticoids, and 14.6% also received additional immunosuppressive drugs. Remission was achieved in all patients. All of the patients with IgAV/HSP in our cohort had skin manifestations, while 18 (60%) had gastrointestinal involvement and 13 (43.3%) had renal involvement. When we compared the features of this subset of 30 patients to those of a pre-pandemic pediatric IgAV/HSP cohort (n = 159), the clinical characteristics of fever and renal involvement were more common in our COVID-19-associated pediatric IgAV/HSP cohort (fever, 30% versus 5%, respectively [P < 0.001]; renal involvement, 43.3% versus 17.6%, respectively [P = 0.002]). Recovery without treatment and complete recovery were each less frequent among our COVID-19-associated pediatric IgAV/HSP patients compared to the pre-pandemic pediatric IgAV/HSP cohort (recovery without treatment, 10% versus 39%, respectively [P = 0.002]; complete recovery, 86.7% versus 99.4%, respectively [P = 0.002]).This is the largest cohort of children with COVID-19-associated vasculitis (excluding MIS-C) studied to date. Our findings suggest that children with COVID-19-associated IgAV/HSP experience a more severe disease course compared to pediatric IgAV/HSP patients before the pandemic.
Highlights from Recent Cancer Literature
Journal: Cancer Research (2022)

Stimulator of interferon genes (STING) agonists rapidly moved into clinical trials with great optimism but have only shown mediocre therapeutic efficacy in patients.Li and colleagues revealed that STING activation in B cells drives immunosuppression that counteracts the stimulatory activity of these drugs, and that blocking regulatory B-cell function can improve STING-based cancer immunotherapy.Using specific deletion of STING (TMEM173) in B cells, they first showed that systemic delivery of STING agonists is more effective in controlling multiple cancer models, most importantly pancreatic ductal adenocarcinomas (PDAC).Next, they found that in response to STING activation, B cells take on a regulatory phenotype and produce two suppressive cytokines, IL35 and IL10.They found that IL35 production is essential for their suppressive nature, acting to suppress natural killer (NK) cell antitumor responses specifically in response to STING agonists.Finally, they showed that a combination of blocking anti-IL35 antibodies in combination with STING agonists leads to effective control of mouse models of PDAC and lung cancer and that PDAC patients, compared with healthy donors, exhibited elevated induction of IL35 in response to STING agonists.
Risk of Overusing Sentinel Node Biopsy in Patients With Thin Melanoma
Authors: Elif Hindié
Journal: Journal of Clinical Oncology (2022)

Moncrieff et al 1 recently reported on results of sentinel node (SN) biopsy in a retrospective study of 3,607 patients with pT1b or pT2a melanoma, who underwent SN biopsy between 2005 and 2020 at nine cancer centers while also assessing the prognostic value of tumor deposit maximum dimension in patients with SN micrometastases.SN biopsy was positive in 408 patients (11.3%).These patients would be classified with stage IIIA disease according to the eighth edition of American Joint Committee on Cancer (AJCC). 2 Survival analysis among SN-positive patients identified a SN tumor deposit maximum dimension of 0.3 mm as the optimal cut point for stratifying survival.Five-year disease-specific survival rates were 80.3% and 94.1% for patients with SN metastatic tumor deposits $ 0.3 mm and , 0.3 mm, respectively (hazard ratio, 1.26 [1.11 to 1.44]; P , .0001).The authors propose that indications for offering adjuvant systemic therapy in patients with AJCC IIIA melanoma should use this cutoff rather than the . 1 mm cutoff currently suggested in many guidelines. 1 The newly identified high-risk ($ 0.3 mm) subgroup comprised 271 (66.4%) patients of the stage IIIA cohort, whereas only 142 (34.8%) patients had SN tumor deposits . 1 mm in maximum dimension.
Current use and future potential of (physiologically based) pharmacokinetic modelling of radiopharmaceuticals: a review
Authors: Hinke Siebinga, Berlinda J. de Wit-van der Veen, Marcel D.M. Stokkel, Alwin D.R. Huitema, Jeroen J.M.A. Hendrikx
Journal: Theranostics (2022)

Rationale: Physiologically based pharmacokinetic (PBPK) and population pharmacokinetic (PK) modelling approaches are widely accepted in non-radiopharmaceutical drug development and research, while there is no major role for these approaches in radiopharmaceutical development yet.In this review, a literature search was performed to specify different research purposes and questions that have previously been answered using both PBPK and population PK modelling for radiopharmaceuticals. Methods: The literature search was performed using the databases PubMed and Embase.Wide search terms included radiopharmaceutical, tracer, radioactivity, physiologically based pharmacokinetic model, PBPK, population pharmacokinetic model and nonlinear mixed-effects model.Results: Eight articles and twenty articles were included for this review based on this literature search for population PK modelling and PBPK modelling, respectively.Included population PK analyses showed to have an added value to develop predictive models for a population and to describe individual variability sources.Main purposes of PBPK models appeared related to optimizing treatment (planning), or more specifically: to find the optimal combination of peptide amount and radioactivity, to optimize treatment planning by reducing the number of measurements, to individualize treatment, to get insights in differences between pre-therapeutic and therapeutic scans or to understand inter-patient differences.Other main research subjects were regarding radiopharmaceutical comparisons, selecting ligands based on their peptide characteristics and gaining a better understanding of drug-drug interactions.Conclusions: The use of PK modelling approaches in radiopharmaceutical research remains scarce, but can be expanded to obtain a better understanding of PK and whole-body distribution of radiopharmaceuticals in general.PK modelling of radiopharmaceuticals has great potential for the nearby future and could contribute to the evolving research of radiopharmaceuticals.
MoDLE: high-performance stochastic modeling of DNA loop extrusion interactions
Authors: Roberto Rossini, Vipin Kumar, Anthony Mathelier, Torbjørn Rognes, Jonas Paulsen
Journal: Genome biology (2022)

Abstract DNA loop extrusion emerges as a key process establishing genome structure and function. We introduce MoDLE, a computational tool for fast, stochastic modeling of molecular contacts from DNA loop extrusion capable of simulating realistic contact patterns genome wide in a few minutes. MoDLE accurately simulates contact maps in concordance with existing molecular dynamics approaches and with Micro-C data and does so orders of magnitude faster than existing approaches. MoDLE runs efficiently on machines ranging from laptops to high performance computing clusters and opens up for exploratory and predictive modeling of 3D genome structure in a wide range of settings.
Elexacaftor/tezacaftor/ivacaftor corrects monocyte microbicidal deficiency in cystic fibrosis
Authors: Luca Cavinato, Francesco R. Luly, Valentina Pastore, Daniele Chiappetta, Gloria Sangiorgi, Eva Ferrara, Pia Baiocchi, Giuseppe Mandarello, Giuseppe Cimino, Paola Del Porto, Fiorentina Ascenzioni
Journal: European Respiratory Journal (2022)

Background Cystic fibrosis (CF), which is caused by mutations in the CF transmembrane conductance regulator (CFTR), is characterised by chronic bacterial lung infection and inflammation. In CF, monocytes and monocyte-derived macrophages have been shown to display defective phagocytosis and antimicrobial activity against relevant lung pathogens, including Pseudomonas aeruginosa . Thus, we addressed the effect of CFTR triple modulator therapy (elexacaftor/tezacaftor/ivacaftor (ETI)) on the activity of CF monocytes against P. aeruginosa . Methods Monocytes from people with CF (PWCF) before and after 1 and 6 months of ETI therapy were isolated from blood and infected with P. aeruginosa to assess phagocytic activity and intracellular bacterial killing. The oxidative burst and interleukin-6 secretion were also determined. Monocytes from healthy controls were also included. Results Longitudinal analysis of the clinical parameters confirmed an improvement of lung function and lung microbiology by ETI. Both the phagocytic and microbicidal deficiencies of CF monocytes also improved significantly, although not completely. Furthermore, we measured an exuberant oxidative burst in CF monocytes before therapy, which was reduced considerably by ETI. This led to an improvement of reactive oxygen species-dependent bactericidal activity. Inflammatory response to bacterial stimuli was also lowered compared with pre-therapy. Conclusions PWCF on ETI therapy, in a real-life setting, in addition to clinical recovery, showed significant improvement in monocyte activity against P. aeruginosa , which may have contributed to the overall effect of ETI on pulmonary disease. This also suggests that CF monocyte dysfunctions may be specifically targeted to ameliorate lung function in CF.
Cognate microglia–T cell interactions shape the functional regulatory T cell pool in experimental autoimmune encephalomyelitis pathology
Authors: Zhana Haimon, Gal Ronit Frumer, Jung-Seok Kim, Sébastien Trzebanski, Rebecca Haffner-Krausz, Shifra Ben-Dor, Ziv Porat, Andreas Muschaweckh, Louise Chappell-Maor, Sigalit Boura-Halfon, Thomas Korn, Steffen Jung
Journal: Nature Immunology (2022)
Bioinspired MoS<sub>2</sub> Nanosheet‐Modified Carbon Fibers for Synergetic Bacterial Elimination and Wound Disinfection
Authors: Yanan Tang, Zhen Qin, Yinghui Zhong, Xianqiang Yan, Liang Kong, Xiangyu Yang, Shengyan Yin, Mo Li, Zhenning Liu, Hang Sun
Journal: Advanced Healthcare Materials (2022)

Bacterial infection is one of the most frequent wound complications and has become a major public health concern. Increasing resistance to antibiotics has been noted with these agents broadly used in wound management. It is an urgent demand to develop alternative antibacterial strategies with a reduced chance of resistance. Herein, a Nepenthes-mimicking nanosheet array of MoS2 on carbon fibers (CF-MoS2 ) is proposed to achieve dual bactericidal activities. First, the sharp edges of synthesized surfaces are capable of inducing physical disruption of cell membranes, demonstrating mechanical antibacterial activity like their natural counterparts. Second, in the presence of near-infrared light, bioinspired CF-MoS2 nanosheets are able to cause the death of damaged bacteria owing to their inherent photothermal properties. Such dual-functional modes endow the surfaces with nearly 100% killing efficiency for highly concentrated Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). Furthermore, their potential to be applied as wound dressings for photothermal treatment of infectious wounds is also investigated in vivo. Bioinspired CF-MoS2 dressings show advantages of synergistic disinfection and efficient promotion of wound regeneration. It is foreseen that this high-performance and multifunctional CF-MoS2 could afford a feasible broad-spectrum treatment for non-antibiotic disinfection.
Correction: <i>TP53</i>-Mutated Myelodysplastic Syndrome and Acute Myeloid Leukemia: Biology, Current Therapy, and Future Directions
Journal: Cancer Discovery (2022)

In Table 1 of the original version of this article (1), some values in the second row (Venetoclax + azacitidine or 5-day decitabine) were omitted or incorrect. “Study phase” should be Ib/II, III, “TP53-mutated pts” should be 36, 54, “Response” should be CR/CRi 47%, 41%, and “CR rate” should be NR, 20%. The values in Table 1 have been corrected in the latest online HTML and PDF versions of the article. The authors regret this error.